ATLANTAIn a phase III trial of patients who had undergone
surgery for rectal cancer, three regimens of fluorouracil (5-FU)-based
chemotherapy and radiation therapy achieved similar rates of relapse-free and
overall survival, although the three regimens had somewhat differing toxicity
profiles.

Lead author Stephen R. Smalley, MD, a radiation oncologist
at the Olathe Regional Oncology Center, Olathe, Kansas, reported the results at
the 46th Annual Meeting of the American Society for Therapeutic Radiology and
Oncology (abstract 14).

Recent trials have found that after surgery for rectal
cancer, protracted venous infusion (PVI) of 5-FU during radiation therapy
improves outcomes relative to bolus infusion (Intergroup 864751), and outcomes
are similar with a variety of different biochemically modulated bolus regimens
of 5-FU (Intergroup 0114), Dr. Smalley said.

The new trial (Intergroup 0144), therefore, sought to answer
three questions, he said: "Number one, would a protracted course of 5-FU (prior
to and following protracted 5-FU and radiation) lead to further improvement in
outcome? Number two, could a biochemically modulated 5-FU program without
central venous catheters produce outcomes similar to those of the protracted
venous infusion arm? And number three, how would pelvic control be affected,
especially in those groups that were most rationally treated with initial
surgery?"

The investigators enrolled patients who had undergone
complete resection of locally advanced but nonmetastatic rectal adenocarcinoma
(T3-4, N0, M0 or T1-4, N1-2, M0) in the prior 20 to 70 days; dentate
involvement was allowed. Patients were required to have adequate organ function
and no prior chemotherapy or radiation therapy.

The patients were stratified by type of resection (abdominoperineal
vs low anterior), T stage, N stage, and time from surgery. They were then
assigned to three treatment arms:

■ Arm 1: Bolus 5-FU
before and after radiation therapy, with 5-FU by PVI during radiation therapy

In all, 1,917 patients were enrolled in the trial, and
living patients had a median follow-up of 6.1 years, making the data mature,
Dr. Smalley noted.

Study Results

The three treatment arms had statistically indistinguishable
rates of overall survival (81% to 83%) and relapse-free survival (67% to 69%)
at 3 years follow-up, Dr. Smalley said. For both endpoints, the findings were
the same in analyses comparing arm 1 with arm 2, and arm 1 plus arm 2 with arm
3. [See the Table for 5-year survival rates.]

"It’s important to evaluate pelvic control, especially for
those patients who are initially appropriately managed by surgery," Dr. Smalley
said, noting that some trials have found better pelvic control with
preoperative radiation therapy, with or without chemotherapy. "However,
preoperative radiotherapy does produce an increased clinically meaningful
toxicity, both gastrointestinal and sexual in nature, and it is obviously
desirable to avoid these side effects in those who are unlikely to benefit from
radiation therapy. This would certainly include patients who are candidates for
sphincter-sparing surgery when they present, as well as patients who do not
have fixed primary rectal lesions."

With the 6.1-year median follow-up, the rate of pelvic
failure was similarly low across treatment arms in the entire study population
(5% to 7%) and in the subgroup of patients who were appropriately managed with
initial surgery, namely those with non-T4b disease who underwent low anterior
surgical resection (3% to 6%).

Toxicity

Patients in arms 1, 2, and 3 had similar rates of
treatment-related death (approximately 1%) and gastrointestinal toxicity of
grade 3 or higher (42% to 46%), Dr. Smalley said.

In contrast, rates of grade 3 or higher hematologic toxicity
differed, with this complication occurring in about half of the patients in
arms 1 and 3 (50% to 56%) but in few patients in arm 2 (4%). "However this was
primarily a laboratory change because the PVI arm [arm 2] had a 6% grade 3-5
infection rate vs 10% to 11% in the two bolus 5-FU arms," Dr. Smalley noted. As
expected, catheter-related toxicity was higher in arms 1 and 2 (2% to 3%) than
in arm 3 (less than 0.5%), he added.

‘Similar Outcomes’

"We conclude that all three dose schedules lead to similar
outcomes following resection," Dr. Smalley commented. "Hematologic toxicity was
definitely decreased with protracted venous infusion, but it must be balanced
against the cost, inconvenience, and risk of catheter-related toxicities with
PVI."

He told ONI that although other recent trials have
found PVI to be superior to bolus therapy, "our trial is by far the biggest and
most satisfactorily powered study, and really suggests that any 5-FU regimen
plus radiation produces similar survival outcomes."

Less Extensive Treatment

The findings further suggest that less extensive treatment
is safe in some patients, Dr. Smalley pointed out. "Initial surgical management
of nonfixed lesions that are amenable to sphincter-preserving surgery at
presentation is entirely justified," he said. "Those patients at low risk of
pelvic recurrence following surgerycertainly this would include T1-2, N0
patients, potentially even selected T3, N0 patientscan avoid the toxicity of
radiation."